迷你器官有望为小肠衰竭的儿童提供治疗

2020/11/23 11:11:55 本站原创 佚名 【字体:

廖联明  编译

 

根据发表在《自然医学》上的一项研究,弗朗西斯·克里克研究所、大奥蒙德街医院(GOSH)和加州大学洛杉矶分校(UCL)大奥蒙德街儿童健康研究所(ICH)的科学家利用患者组织中的干细胞培育出人体肠道可移植组织,有朝一日,这些干细胞可以为肠道衰竭的儿童进行个性化移植。

肠道衰竭的儿童无法吸收对其整体健康和发展至关重要的营养物质。这可能是由于小肠疾病或损伤所致。

在这些情况下,儿童可以通过静脉注射的方式(称为肠外营养)获得营养,但这会出现严重的并发症,如血行感染和肝衰竭。如果出现这些并发症甚至情况更严重,这些儿童就可能需要移植。然而,缺乏合适的供体器官,而且手术后可能会出现一些问题,例如排斥反应。
在他们的理论验证研究中,研究小组展示了从病人身上提取的肠道干细胞和小肠或结肠组织,如何在实验室中培养出小肠重要的内皮层,内皮层具有消化和吸收肽和消化食物中蔗糖的能力。
这是为移植而设计肠道各层的第一步。研究人员希望有一天,实验室培养的器官能够提供一种安全、持久的组织替代传统的供者移植。

研究人员对12名患有肠道衰竭或有肠道衰竭风险的儿童进行了小肠活检。在实验室里,他们刺激活检细胞成长为“微型肠道”,也称为肠类器官。

研究人员还收集了其他接受必要手术切除部分肠道的儿童的小肠和结肠组织。利用实验室技术,从这些组织中取出细胞,留下一个骨架结构,形成支架。
研究人员把这些“小内脏”放在这些支架上,在支架上生长,形成一个活的移植物。由于特定的培养条件,干细胞变成了许多存在于小肠中的不同类型的细胞。移植物能够消化和吸收肽,即蛋白质的组成部分,以及将蔗糖消化成葡萄糖。

“尽管这项研究目前还在实验室中,但我们正致力于使其成为一种现实和安全的治疗选择,”国立卫生研究院(NIHR)的资深教授保罗·德科皮(Paolo De Coppi)解释道,他是GOSH的儿科医生,也是UCL大奥蒙德街儿童健康研究所(ICH)的外科、干细胞和再生医学科主任。

“重要的是我们已经证明了支架可以用结肠组织而不仅仅是小肠组织来制造。实际上,从结肠获取组织通常更容易,因此这可能使该方法更加可行。这是再生医学向前迈出的重要一步,我们对这对患者意味着什么感到乐观,但在我们能够安全有效地将这种治疗方法转化为治疗方法之前,还有更多的研究要做。”

除了证明从儿童身上取下的活检可以用来培养功能正常的肠道移植物外,研究人员还证明了移植到小鼠体内后,移植物仍然能够存活并成熟。

现在,他们已经证明移植在小规模上是成功的,下一个关键步骤将是开始生长肠的其他层,如肌肉和血管,同时也扩大他们的方法,培养出与患者个人需求相关的可行移植物。

 

英文原文:

Mini-organs could offer treatment hope for children with intestinal failure

 

Pioneering scientists at the Francis Crick Institute, Great Ormond Street Hospital (GOSH) and UCL Great Ormond Street Institute of Child Health (ICH) have grown human intestinal grafts using stem cells from patient tissue that could one day lead to personalised transplants for children with intestinal failure, according to a study published in Nature Medicine.

Children with intestinal failure cannot absorb the nutrients that are essential for their overall health and development. This may be due to a disease or injury to their small intestine.

In these cases, children can be fed intravenously via a process called parenteral nutrition, however this is associated with severe complications such as line infections and liver failure. If complications arise or in severe cases these children may need a transplant. However, there is a shortage of suitable donor organs and problems can arise after surgery, such as the body rejecting the transplant.In their proof-of-concept study, the research team showed how intestinal stem cells and small intestinal or colonic tissue taken from patients can be used to grow the important inner layer of small intestine in the laboratory with the capacity to digest and absorb peptides and digest sucrose in food.

This is the first step in efforts to engineer all the layers of the intestine for transplantation. The researchers hope that one day, laboratory grown organs could offer a safe and longer-lasting alternative to traditional donor transplants.

 

The researchers took small biopsies of intestine from 12 children who either had intestinal failure or were at risk of developing the condition. In the lab, they then stimulated the biopsy cells to grow into "mini-guts," also known as intestinal organoids.

The researchers also collected small intestine and colon tissue, that would otherwise have been discarded, from other children undergoing essential surgery to remove parts of their gut. Using laboratory techniques, cells were removed from these tissues leaving behind a skeleton structure which formed scaffolds.

The researchers placed the "mini-guts" onto these scaffolds, where they grew on this structure to form a living graft. Due to specific culture conditions, the stem cells changed into many of the different types of cells that exist in the small intestine. The grafts were able to digest and absorb peptides, the building blocks of proteins, as well as digest sucrose into glucose sugars.

"Although this research is in the lab right now, we're concentrating on making this a realistic and safe treatment option," explains senior author NIHR Professor Paolo De Coppi, Consultant Paediatric Surgeon at GOSH and Head of Surgery, Stem Cells & Regenerative Medicine Section at the UCL Great Ormond Street Institute of Child Health (ICH).

"What's significant here is we've shown that scaffolds can be created using tissue from the colon, not only tissue from the small intestine. In practice, it is often easier to obtain tissue from the colon, so this could make the approach much more feasible. It's an important step forward in regenerative medicine and we're optimistic about what this means for patients, but more research lies ahead before we can safely and effectively translate this approach to treatment."

As well as proving that biopsies taken from children could be used to grow functioning intestinal grafts, the researchers also demonstrated that the grafts survive and mature when transplanted into mice.

Now that they've shown the grafts are successful on a small scale, the next crucial steps will be to start growing the other layers of the intestine such as muscle and blood vessels, whilst also scaling up our methods to create viable grafts relevant to individual patient needs.

 

Journal Reference:

Engineering transplantable jejunal mucosal grafts using patient-derived organoids from children with intestinal failure. Nature Medicine, 2020; DOI: 10.1038/s41591-020-1024-z

 

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